1. Field of the Invention
The present invention relates to low-substituted hydroxypropyl cellulose used as an additive for medicines, agrochemicals or food, a solid formulation (preparation) containing the same and a process for manufacturing the same.
2. Description of the Related Art
Solid formulations such as tablets and granules are used for medicines, agrochemicals, food and other industrial products. In general, they are used in the form of a granular formulation or a fine granule formulation which is prepared by mixing a principal component with an additive such as filler, a disintegrant, a binder or the like and tableting the mixture, or adding water and a binder to the mixture thereof, stirring or kneading it and then preparing particles therefrom.
Low-substituted hydroxypropyl cellulose (hereinafter also referred to as xe2x80x9cL-HPCxe2x80x9d) described in the Japanese Pharmacopoeia is used as both a disintegrant and a binder in these solid formulations (Japanese Patent Publication (JP-B) No. 48-38858/1973 (U.S. Pat. No. 3,852,421), Japanese Patent Publication (JP-B) No. 51-19017/1976, Japanese Patent Publication (JP-B) No. 57-53100/1982 (U.S. Pat. No. 4,091,205) and Japanese Patent Provisional Publication (JP-A) No. 7-324101/1995).
L-HPC is a kind of cellulose ethers and similar to hydroxypropyl cellulose (hereinafter also referred to as xe2x80x9cHPCxe2x80x9d) which is generally used as a binder. However, L-HPC has a different property. That is, an essential difference between HPC and L-HPC resides in a content of hydroxypropoxyl groups, and the value thereof is 53.4 to 77.5% in HPC but 5 to 16% in L-HPC. This value is determined by a method described in the Japanese Pharmacopoeia, and a range thereof is distinctly prescribed in a monograph of the Japanese Pharmacopoeia xe2x80x9clow-substituted hydroxypropyl cellulosexe2x80x9d.
However, those which have so far been commercially available as L-HPC have a loose bulk density of about 0.3 g/ml and is poor in a fluidity of powder, so that the following problems have existed. First, granules prepared by fluid bed granulation, have a lower bulk density than a L-HPC powder, so that the fluidity is reduced. When a hard capsule is charged with the above granules to prepare a capsule formulation, it becomes impossible to charge the capsule with the desired amount. Further, in a process for manufacturing tablets by tableting the granules, tableting at a high speed increases a weight deviation of the tablets because of a bulkiness and a poor fluidity thereof.
Further, a fundamental problem resides in that when a particularly large amount of L-HPC is added, fluid bed granulation itself becomes difficult. This is due to the fact that the powder absorbs moisture and swells during granulation to increase in a bulk and flowing is stopped or becomes inferior, so that the particle size distribution becomes quite uneven.
Further, there has been as well the problem that a formulation containing L-HPC is inferior in a feeling on a tongue.
An object of the present invention is to provide a low-substituted hydroxypropyl cellulose which allows the granules to be dense and rich in fluidity and can be increased in an amount thereof when a hard capsule is charged therewith, resulting in reduction of a weight deviation in making tablets at a high speed. In additon, it includes improvement of a feeling on a tongue of the resulting formulation and ease of problems in fluid bed granulation such as a stop of flow. It also includes providing a solid formulation (prepartion) containing the same and a process for manufacturing the same.
Intensive investigations by the present inventors in order to solve the problems described above have resulted in finding that use of low-substituted hydroxypropyl cellulose obtained by further pulverizing the low-substituted hydroxypropyl cellulose having a loose bulk density of 0.40 g/ml or more and a tapped bulk density of 0.60 g/ml or more, which is obtained in a first pulverization process, improves the fluidity and the feeling on the tongue, reduces a weight deviation in making tablets at a high speed, decreases problems such as a stop in flowing in the fluid bed granulation, and can ease the problem of the weight deviation even if a content of L-HPC is elevated in direct compression. Thus, they have come to complete the present invention.
That is, provided are a process for manufacturing a low-substituted hydroxypropyl cellulose, comprising:
a step for dipping a pulp in an alkaline solution to prepare an alkali cellulose,
a step for reacting said alkali cellulose with a hydroxypropylating agent such as propylene oxide to yield a product in a complete dissolution state thereof,
a step for neutralization with an acid to yield a precipitate,
a step for washing,
a step for drying, and
a step for pulverization to yield a powder having a volume-average particle diameter of less than 25 microns which is determined by a dry laser diffraction method, a loose bulk density of 0.29 g/ml or more and less than 0.40 g/ml, and a tapped bulk density of 0.55 g/ml or more, and the low-substituted hydroxypropyl cellulose. Further, provided is a solid formulation containing the low-substituted hydroxypropyl cellulose.
According to the present invention, the granules become dense and are rich in fluidity as compared with those obtained by using conventional L-HPC; when a hard capsule is charged with them, the amount thereof can be raised, and the weight deviation is reduced in making tablets at a high speed; in addition, the resulting formulation is improved in a feeling on a tongue.
Further, the problems in fluid bed granulation such as a stop of flow are reduced, and a problem of a weight deviation in a direct compression process is eased even if a content of L-HPC is elevated.
The xe2x80x9cloose bulk densityxe2x80x9d used in the present invention means a bulk density in a loosely filled state and is determined by evenly charging a cylindrical vessel having a diameter of 5.03 cm and a height of 5.03 cm (capacity: 100ml) with a sample through a sieve of 22 mesh (710 xcexcm) of Japanese Industrial Standard (JIS) from an upper part thereof (23 cm above the vessel) and leveling the sample by cutting at the top face of the vessel for weighing it.
On the other hand, the xe2x80x9ctapped bulk densityxe2x80x9d means a bulk density in a densely filled state by additional tapping on the above sample. Tapping is an operation in which the vessel charged with the sample is repeatedly dropped from a fixed height so as to obtain the sample in a densely filled state by applying light impact to the bottom thereof. In practice, after the sample is leveled by cutting at a top face of a vessel for weighing to obtain a loose bulk density, the vessel is fitted with a special-purpose cap supplied together with the powder tester by Hosokawa Micron Co., Ltd. Then, the sample is added up to the top bounds thereof and then 180 times of tapping are carried out at a tapping height of 1.8 cm. Subsequently, the cap is removed, and the sample is leveled by cutting at the top face of the vessel for weighing. The tapped bulk density is obtained as the bulk density in this state. These operations can be carried out by means of the powder tester (PT-D) manufactured by Hosokawa Micron Co., Ltd.
The L-HPC of the present invention can be produced by a method described below.
First, a pulp is dipped in an alkaline solution to prepare an alkali cellulose, and the obtained alkali cellulose is reacted with a hydroxypropylating agent such as propylene oxide. A process up to this stage is the same process as a conventional process for manufacturing L-HPC. In a step subsequent thereto, the product is placed into water or water adjusted to alkalinity and dissolved therein to prepare an almost homogeneous opaque slurry, and then neutralized with hydrochloric acid to recover deposited L-HPC. The recovered L-HPC is washed with water, dryed and pulverized.
In a conventional process, neutralization is partially carried out to obtain a semi-dissolution state by keeping dissolution incomplete. The bulk density is ruled by a fiber content which is varied by conrolling the semi-dissolution state. In the present invention, however, the product is turned into a complete dissolution state, whereby the intended L-HPC is obtained.
The complete dissolution state in this invetion means a state in which the product loses a shape thereof almost completely. That is, it includes, as well as the state in which the solution becomes completely transparent, an opaque slurry state and the state in which small lumps of the product are observed to remain in a proportion of 5 to 10 pieces in a 3-liter slurry. Since the post-dissolution state is in a form of slurry having a high viscosity, a mixer having a strong stirring power such as a kneader is required. Then, neutralization is carried out with an acid such as hydrochloric acid as is the case with a conventional method, whereby L-HPC is deposited. The deposited L-HPC is recovered, washed, dried and pulverized to obtain a finised product.
Incidentally, it has been found that complete dissolution of the product is effected by preparation conditions of an alkali cellulose, wherein the complete dissolution state is liable to be obtained, particularly when the alkaline solution for dipping is a sodium hydroxide solution having a concentration of 45% by weight or lower. It can be considered that reduction of a sodium hydroxide concentration from the conventional 49% by weight sodium hydroxide solution, increases homogeneity of the reaction so that the solubiliy inreases.
The pulverizaton step is carried out by two stages, and an intermediate obtained by the first pulverization is preferably L-HPC having a loose bulk density of 0.40 g/ml or more and a tapped bulk density of 0.60 g/ml or more. Thus, re-pulverization of L-HPC having a specified bulk density has the following advantages, even if L-HPC finally obtained does not have a loose bulk density of 0.40 g/ml or more and a tapped bulk density of 0.60 g/ml or more. The obtained granules become dense and is rich in fluidity. When a hard capsule is charged with it, the amount thereof can be increased. The weight deviation is reduced in making tablets at a high speed. In addition, a feeling on a tongue of the resulting formulation is improved.
Further, when fluid bed granulation is carried out, problems such as a stop of flow are reduced. In direct compression, a problem of a weight deviation is eased even if a content of L-HPC is elevated.
A range of a volume-average particle diameter of the intermediate obtained by the first pulvation is not specifically restricted. However, because of a pulverization capacity or the like, the volume-average particle diameter which is determined by a dry laser diffraction method is preferably 30 microns or more.
The first pulvelization stage can be carried out by means of a pulverizer such as a ball mill, a hammer mill or a knife mil, and the second pulverization stage can be carried out by means of a pulverizer suitable for yielding fine powder such as a jet mill.
L-HPC obtained by such methods has a higher density than conventional ones. L-HPC having a volume-average particle diameter of less than 25 microns which is determined by a dry laser diffraction method, a loose bulk density of 0.29 g/ml or more and less than 0.40 g/ml, and a tapped bulk density of 0.55 g/ml or more, are particularly preferable, since a granulation product obtained particularly by fluid bed granulation has a good quality.
The dry laser diffraction method described in the present invention means a method, as is the method in use of a HELOS apparatus manufactured by Sympatec Co., Ltd. in Germany, in which a powder sample blown by means of compressed air is irradiated with a laser beam for determination of a volume-average particle diameter by a diffraction intensity thereof. According to, for example, page 88 of xe2x80x9cKaitei Zoho Funtai Bussei Zusetsu (revised and enlarged editition of Illustration of Powder Propertiesxe2x80x9d edited by Funtai Kogakukai and Nippon Funtai Kogyogijutsu Kyokai, published by Nikkei Gijutsu Tosho Co, Ltd., 1985, the volulme-average particle diameter (size) is calculated by {xcexa3(nD3)/xcexa3n}⅓ wherein D is a particle diameter, n is the number of particles having the particle diameter, and xcexa3 n is a total number of particles.
The present invention is not restricted to an embodiment comprising the two stage pulverization step described above as long as an intended low-substituted hydroxypropyl cellulose can finally be obtained and may include an embodiment comprising the other two stage pulverization step or a single stage pulverization step. However, when pulverization is carried out by two stages, a quality of the pulverized product at the first stage can be controlled, and therefore there are the merits that the finished product has a stabilized quality and a load is less liable to be exerted on a pulverizer.
The solid formulation in the present invention means a tablet formulation, a granular formulation, a fine granule formulation and a capsule formulation. Any method such as direct compression, wet tableting, dry granulation and fluid bed granulation can be applied to a production process for these solid formulations.
Direct compression is carried out by mixing a principal component with an additive and tableting the mixture as it is. Wet tableting is carried out by mixing a mixture of a principal component and an additive with a binder solution or a suitable solvent such as water for granulation, then drying, and tableting. When the principal component or an additive is inferior powder in fluidity, the latter is carried out for the purpose of elevating the fluidity thereof.
Dry granulation is carried out when a principal component is instable in the presence of water, wherein a principal component is mixed with an additive, compressed by a roller compactor, pulverized and granulated. A granular formulation and a fine granule formulation are used as they are after wet or dry granulation, or those produced by mixing a mixture of a principal component and an additive with water or a binder solution, extrusion-molding the obtained mixture by means of a screen, and then pulverizing and granulating it. The capsule formulation is produced by charging granules or fine granins into a hard capsule made of gelatin or a cellulose derivative.
A main granulation process in a wet granulation method for a tablet formulation, a granular formulation or a fine granule formulation, includes agitation granulation using a high-speed mixer and fluid bed granulation using a fluid bed.
The fluid bed granulation is preferably carried out in recent years in terms of a narrower particle size distribution of the granulated product and easiness in a step control, as compared with the agitation granulation. However, if conventional L-HPC is used in the fluid bed granulation, a very bulky granulated product is obtained, havig a inferity in fluidity. Thus, the obtained powder do not flow out from a hopper of a tableting machine, making tableting impossible, or a weight deviation of the tablets is notably increased. However, the L-HPC of the present invention is characterized by that it can be suitable for the fluid bed granulation.
An amount of L-HPC contained in these solid formulations is suitably determined according to an added quantity and quality of a principal component.
The principal component added to the solid formulation is not particularly restricted and may include medicines such as antipyretic analgesic agents, antibiotics or antiphlogistic agents, foods such as vitamins or nutrients, and others such as agrochemicals or detergents. Further, if necessary, disintegrants, binders, fillers or lubricants, which are other additives, may be added.